Abstract
Overexpression of the Bcl-2 proto-oncogene in tumor cells confers resistance against chemotherapeutic drugs. In this study, we describe how the novel pyrrolo-1,5-benzoxazepine compound 7-[[dimethylcarbamoyl]oxy]-6-(2-naphthyl)pyrrolo-[2,1-d] (1,5)-benzoxazepine (PBOX-6) selectively induces apoptosis in Bcl-2-overexpressing cancer cells, whereas it shows no cytotoxic effect on normal peripheral blood mononuclear cells. PBOX-6 overcomes Bcl-2-mediated resistance to apoptosis in chronic myelogenous leukemia (CML) K562 cells by the time- and dose-dependent phosphorylation and inactivation of antiapoptotic Bcl-2 family members Bcl-2 and Bcl-XL. PBOX-6 also induces Bcl-2 phosphorylation and apoptosis in wild-type T leukemia CEM cells and cells overexpressing Bcl-2. This is in contrast to chemotherapeutic agents such as etoposide, actinomycin D, and ultraviolet irradiation, whereby overexpression of Bcl-2 confers resistance against apoptosis. In addition, PBOX-6 induces Bcl-2 phosphorylation and apoptosis in wild-type Jurkat acute lymphoblastic leukemia cells and cells overexpressing Bcl-2. However, Jurkat cells containing a Bcl-2 triple mutant, whereby the principal Bcl-2 phosphorylation sites are mutated to alanine, demonstrate resistance against Bcl-2 phosphorylation and apoptosis. PBOX-6 also induces the early and transient activation of c-Jun NH2-terminal kinase (JNK) in CEM cells. Inhibition of JNK activity prevents Bcl-2 phosphorylation and apoptosis, implicating JNK in the upstream signaling pathway leading to Bcl-2 phosphorylation. Collectively, these findings identify Bcl-2 phosphorylation and inactivation as a critical step in the apoptotic pathway induced by PBOX-6 and highlight its potential as an effective antileukemic agent.
Original language | English |
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Pages (from-to) | 1084-95 |
Number of pages | 12 |
Journal | The Journal of pharmacology and experimental therapeutics |
Volume | 310 |
Issue number | 3 |
DOIs | |
Publication status | Published - Sept 2004 |
Keywords
- Antibiotics, Antineoplastic
- Antineoplastic Agents
- Apoptosis
- Carbazoles
- Dactinomycin
- Drug Resistance, Neoplasm
- Etoposide
- Humans
- Indoles
- JNK Mitogen-Activated Protein Kinases
- Jurkat Cells
- K562 Cells
- Leukemia
- Leukocytes, Mononuclear
- Mitogen-Activated Protein Kinases
- Oxazepines
- Phosphorylation
- Proto-Oncogene Proteins
- Proto-Oncogene Proteins c-bcl-2
- Pyrroles
- Subcellular Fractions
- Tumor Cells, Cultured
- Ultraviolet Rays
- bcl-2-Associated X Protein
- bcl-X Protein